The long-term objective of this work is to determine the role of heparan sulfate in regulating osteolytic bone metastasis and to use this knowledge to develop novel therapies. Heparan sulfates bind to, and regulate the function of, a host of effector molecules that control cell signaling (e.g., growth factors, chemokines), including factors that regulate metastasis and osteolysis. Recent studies demonstrate that heparanase mediated cleavage of heparan sulfate enhances the biological activity of heparan sulfate by releasing fragments 10-20 sugar residues long that potentiate the activity of growth factors better than do intact heparan sulfate chains. Heparanase activity promotes angiogenesis and metastasis in some tumors and elevated expression of heparanase is associated with a poor prognosis in some types of cancer. However, the role of heparanase in osteolytic metastasis is wholly unknown. We have made several striking discoveries supporting the hypothesis that elevated expression of heparanase in multiple myeloma and breast cancer promotes osteolytic bone metastasis. Our immediate goal is to test this hypothesis by enhancing heparanase expression in tumor cells and testing their growth, metastatic and osteolytic behavior in animal models including a new model in which cells with elevated heparanase spontaneously metastasize from subcutaneous sites to bone. This goal will be accomplished by execution of three specific aims using both myeloma and breast cancer cells. Aim 1: Animal models of both spontaneous and experimental metastasis will be used to determine the effect of elevated heparanase expression on metastasis to bone. Aim 2: Tumor cells will be directly injected into bone and the effect of elevated heparanase expression on the growth of tumor within the bone and on bone turnover will be analyzed. In addition, the mechanism of heparanase action will be examined both in vivo and in vitro, including examining the effect of heparanase activity on osteoclast-stimulating factors. Aim 3: Inhibitors of heparanase will be tested in the animal models to examine the potential therapeutic effects of these compounds and to confirm the role of heparanase in osteolytic metastasis. This work will provide a comprehensive understanding of how heparanase and degradation of heparan sulfate regulates osteolytic bone metastasis and holds potential for discovery of new therapeutic targets for controlling tumors within bone.